A Trial of EPIC Proportions

Study Title: A Phase IIIb Clinical Study to Assess Whether Regular Administration of F.VIII in the Absence of Immunological Danger Signals Reduces the Incidence Rate of Inhibitors in Previously Untreated Patients with Hemophilia A (The EPIC Trial)

Coordinator: Baxter Healthcare Corporation

Clinicaltrials.gov Identifier: NCT01376700

Participating Centers: 75 centers planned: 27 enlisted to date, including 20 in six European countries and seven in two Asian countries

Accrual Goal: 100 patients

Study Design: This is a prospective, open-label, singlearm trial designed to test whether low-dose factor VIII (F.VIII), started at an early age, before the onset of severe bleeding and in the absence of other “danger” signals (e.g., infection or trauma), can reduce the incidence of inhibitors. Those who are eligible to participate in this trial include males, age &lt; 1 year, with severe or moderately severe hemophilia A (F.VIII &lt; 2%), with three or fewer past exposures to F.VIII and adequate venous access without central line requirement. All subjects will receive 25 IU/kg of recombinant F.VIII once weekly by intravenous infusion for up to two years. For head injury, preventive low-dose F.VIII will be allowed. For a joint bleed, the dose may be escalated to twice weekly. The primary endpoint is the incidence of inhibitor formation within the first 50 F.VIII exposure days. Secondary endpoints include time-to-inhibitor formation, antibody titer, antibody isotype, bleeding, adverse event frequency, and documentation of risk factors for inhibitor formation including VIII genotype, HLA haplotype, F.VIII consumption, and immunologic markers.

Rationale: F.VIII inhibitor formation in patients with hemophilia A is a challenging clinical problem associated with major morbidity and high cost. Current hypotheses postulate that inhibitors form when early exposure to F.VIII occurs in the presence of “danger” signals (e.g., hemorrhage, infection, or trauma). Under these conditions, the immune system is activated, increasing the probability of inhibitor formation. A pilot trial of once-weekly F.VIII in 26 previously untreated children with severe hemophilia A reported an inhibitor rate of 3.4 percent (Kurnik K et al. Haemophilia. 2010;16:256-262). Though limited by size, variable follow-up, and patient selection, this approach suggested that induction of tolerance to F.VIII could be achieved. The EPIC study is the first prospective, multicenter trial to determine if low-dose factor given before the first bleeding episode will prevent or reduce inhibitor formation. It will also collect immunologic and genetic marker data to better understand the basis of F.VIII tolerance (Matsui H. Blood. 2009;114:677-685).

Comment: Risk factors for hemophilia inhibitor formation have been well-established, but it is still difficult to identify prospectively the 25 percent of patients in whom inhibitors will develop. Most commonly, inhibitors develop during the first 50 F.VIII exposure days, hence the rationale for attempting to induce tolerance by exposing very young patients (&lt; 1 year old) to lowdose recombinant F.VIII. If the innovative “pre-emptive” approach proposed by the EPIC trial is successful, such a preventive strategy will be potentially practice-changing and will set the standard for future randomized trials.